ABSTRACT
Background: Adult recipients of hematopoietic cell transplantation (HCT) are at a very high risk of adverse outcomes after COVID-19 (Sharma A, Bhatt NS, et al. Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an observational cohort study. The Lancet Haematology. 2021 Mar 1;8(3): e185-93). While children are known to have better outcomes after COVID-19 compared to adults in general, data on risk factors and outcomes of COVID-19 among pediatric recipients of HCT are lacking. Methods: Using the data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between March 2020 and May 2021, we describe characteristics, severity, treatment approaches, and outcomes of pediatric HCT recipients who were ≤21 years of age at COVID-19 diagnosis. All diagnoses, donor choice/graft sources, and conditioning regimens were included. Patient, disease, and HCT-related factors were described as frequency for categorical variables and median, range, and interquartile range (IQR) for continuous variables. The probability of overall survival after COVID-19 was calculated using the Kaplan Meier estimator. Additionally, an analysis was performed in the subset of allogeneic HCT COVID-19 cases from the United States (US) to identify risk factors for developing COVID-19. COVID-19 cases were compared with a cohort of all pediatric allogeneic HCT recipients without COVID-19 matched by the transplant center. Impact of hematopoietic cell transplant comorbidity index (HCT-CI), HCT indication, donor type, conditioning intensity, graft vs. host disease (GVHD) prophylaxis, and occurrence of acute and chronic GVHD on development of COVID-19 was examined using Cox proportional hazards model. Hazard ratio (HR) and 95% confidence intervals (CI) were provided. Cumulative incidence of COVID-19 among the US centers reporting at least 1 COVID-19 infection was also calculated, using death from any cause as a competing risk. P value <0.05 was considered statistically significant for the analyses. Results: A total of 167 pediatric HCT recipients (allogeneic, allo: 135 and autologous, auto: 32) met study inclusion criteria. Median age at COVID-19 diagnosis for allo and auto HCT recipients were 15 years (range <1-21y) and 7 years (range 1-21y), respectively. Median time from HCT to COVID-19 diagnosis was 15 months (IQR 7-45) for allo recipients and 16 months (IQR 6-59) for auto HCT recipients. Forty-two percent (42%) of the patients had at least one comorbidity prior to HCT. Thirteen percent (13%) were receiving immunosuppression within six months prior to COVID-19 diagnosis. COVID-19 disease severity was mild in 87% of patients, while 4% of patients had severe disease requiring mechanical ventilation or supplemental oxygen. Only 36 HCT recipients (22%) received any COVID-19 directed therapy. Median follow-up from COVID-19 diagnosis was 53 days (range 1-270) and 37 days (range 1-179) for allo and auto HCT recipients, respectively. The overall probability of survival at 45 days was 95% (95% CI 90-99%) and 90% (95% CI 74-99%) for allo and auto HCT recipients, respectively (Figure 1). Forty-five (45) day survival was lower among recipients transplanted at the transplant centers outside the US [non-US recipients 85% (95% CI 71-95%) versus US recipients 98% (95% CI 93-99%)]. No deaths occurred in patients who had received a transplant between 2000-2013. The primary cause of death was COVID-19 in 54% of patients and primary disease in 38% of patients. In the subset analysis restricted to pediatric allogeneic HCT recipients transplanted at the US centers (n=34), the cumulative incidence of COVID-19 infection was noted to be 1.9% (95% CI 1.2-2.9%) at 6 months post-HCT and increased to 4.7% (95% CI 3.4-6.3%) by 1-year post-HCT. Cox regression analysis showed that compared to HCT-CI score of 0, patients with HCT-CI score of 1-2 were more likely to develop COVID-19 (HR 1.95;95% CI 1.03-3.69, p=0.042). Underlying diagnosis, donor type, treatment exposures, or GVHD did not predict COVID- 9 incidence. Conclusions: This is the largest series to date summarizing the cumulative incidence, risk factors, and outcomes of pediatric HCT recipients with COVID-19. Patients with pre-HCT comorbidities were more likely to develop COVID-19. However, the overall disease severity and mortality after COVID-19 were low in this patient cohort. [Formula presented] Disclosures: Bhatt: Rite Aid Corporation: Divested equity in a private or publicly-traded company in the past 24 months;Pfizer Inc.: Divested equity in a private or publicly-traded company in the past 24 months;Moderna, Inc.: Divested equity in a private or publicly-traded company in the past 24 months;Johnson & Johnson: Divested equity in a private or publicly-traded company in the past 24 months. Sharma: Medexus Inc: Consultancy;Spotlight Therapeutics: Consultancy;Vindico Medical Education: Honoraria;CRISPR Therapeutics: Other, Research Funding;Novartis: Other: Salary support paid to institution;Vertex Pharmaceuticals/CRISPR Therapeutics: Other: Salary support paid to institution. Riches: ATARA Biotherapeutics: Other: Payment;Jazz Pharmaceuticals: Other: Payment;BioIntelect: Membership on an entity's Board of Directors or advisory committees. Dandoy: Omeros: Other: Consulted and received Honorarium.
ABSTRACT
[Formula presented] Introduction: During the COVID-19 pandemic, concerns regarding travel logistics and donor safety necessitated a substantial increase in the use of cryopreserved hematopoietic stem cell (HSC) grafts from both related (RD) and unrelated donors (URD) to ensure patients have a graft available prior to the start of conditioning for hematopoietic cell transplantation (HCT). However, pre-pandemic data beyond single center or small multi-center reports are lacking to reassure clinicians that cryopreservation of allogeneic grafts does not adversely impact post-HCT outcomes including hematopoietic engraftment and overall survival (OS). The Center for International Blood and Marrow Transplant Research (CIBMTR) has recently published three retrospective analyses of outcomes in recipients of cryopreserved compared to fresh grafts administered prior to the pandemic. Results have been conflicting and reasons for receipt of cryopreserved grafts were not routinely collected, rendering interpretation of the impact of cryopreservation on clinical outcomes problematic. Since the pandemic provided a unifying rationale (including mandatory cryopreservation required by the National Marrow Donor Program (NMDP) and other major registries) for the majority of patients to receive cryopreserved allografts, we sought to evaluate early post-HCT clinical outcomes in patients reported to the CIBMTR database who received a first allogeneic HCT using cryopreserved grafts from March through August 2020. Methods: Key study endpoints were hematopoietic engraftment and overall survival (OS). We compared these outcomes to those in patients allografted using fresh products transplanted between March through August 2019. Additional patient selection criteria included: 1) recipients in US only, 2) peripheral blood stem cell (PBSC) or bone marrow (BM) grafts, 3) consented to research, and 4) availability of both CIBMTR product infusion and post-HCT day 100 (D100) follow-up form. The Pearson chi-square test was used for comparing discrete variables;the Kruskal-Wallis test was used for comparing continuous variables. Multivariate analysis (MVA) using a Cox proportional hazards model was performed for OS after adjusting for confounders and testing the proportional hazards assumption. Neutrophil engraftment by D28 and platelet engraftment by D100 were analyzed using multivariate logistic regression. Results: This study included 959 and 2,499 recipients of cryopreserved and fresh products, respectively. Patient characteristics are presented in Table 1. Recipients of cryopreserved grafts were older, more likely to receive URD grafts, PBSC as the graft source and post-transplant cyclophosphamide (PTCy) for graft versus host disease (GVHD) prophylaxis. They received lower infused PBSC and BM cell doses. Due to differences in duration of follow-up between the cohorts, follow up for the OS analysis was censored at Days 100 and 180. MVA results are presented in Table 2. No impact of cryopreservation on OS at either D100 (HR 0.93, p=0.72) or D180 (HR 1.10, p=0.34) post HCT was detected (see also Figure 1). When we performed the MVA for OS limiting the analysis to URD recipients only, the results were unchanged. Median time to neutrophil and platelet engraftment were both delayed by 1 day in recipients of cryopreserved grafts (16 vs. 15 days and 21 vs. 20 days, respectively) but there was no difference in the risk of primary graft failure by D28 (OR 1.38, p=0.96). Some delay in D100 platelet engraftment was observed in recipients of cryopreserved grafts (OR 0.67, p<0.005). There were no interactions identified between donor or graft type for OS or engraftment. Other important clinical outcomes such as secondary graft failure, acute GVHD, and early relapse are being analyzed and will be included at the time of presentation. Conclusion: The shift in clinical practice to cryopreserved products necessitated during the pandemic did not adversely impact early post HCT OS or risk of primary graft failure. We caution that follow up is short and it ill be critical to follow this cohort and subsequent recipients of cryopreserved grafts for much longer periods to determine the ultimate impact of cryopreservation on outcomes. Nevertheless, this large multi-center study will be useful to inform clinical decision making both during and following the pandemic. [Formula presented] Disclosures: Devine: Sanofi: Consultancy, Research Funding;Magenta Therapeutics: Current Employment, Research Funding;Tmunity: Current Employment, Research Funding;Vor Bio: Research Funding;Kiadis: Consultancy, Research Funding;Johnsonand Johnson: Consultancy, Research Funding;Orca Bio: Consultancy, Research Funding;Be the Match: Current Employment. Stefanski: Novartis: Honoraria. Shaw: mallinkrodt: Other: payments;Orca bio: Consultancy.
ABSTRACT
The COVID-19 pandemic posed numerous logistical challenges in the way that the National Marrow Donor Program (NMDP) delivered allogeneic products to patients undergoing hematopoietic cell transplant (HCT). Prior to COVID-19, fresh bone marrow (BM) and peripheral blood stem cell (PBSC) grafts were infused into patients at the time of transplant in more than 90% of cases. Due to the pandemic, graft products could no longer be reliably delivered fresh and required cryopreservation given patient safety issues as well as logistical issues in ensuring timely delivery of a fresh product. Given these challenges, the NMDP as well as other donor registries pivoted to providing cryopreserved products. We sought to evaluate the effect of cryopreservation on the infusion of allogeneic products, analyzing all allogeneic products collected from March 17, 2020 through June 30, 2021. A total of 9294 products were collected from both related donors (RDs) and unrelated donors (URDs). Of these, a total of 8702 products were infused both domestically and internationally: 476 were RDs and 8226 were URDs. One main difference between fresh and cryopreserved products is that transplant centers (TCs) can wait to infuse the product depending on the status of the patient, patient's preference of when to receive HCT, and other factors. Moreover, TCs also can assess the product quality both at the time of product receipt and after cryopreservation thaw, thereby allowing the TC to determine if they will infuse a patient based on product quality. Due to this nuance for cryopreservation, 370 products are pending infusion. Over the last 18 months, only 222 products were not infused for a variety of reasons including patient death, patient choice, poor product quality (low cell counts, clumps in the product, viability or a positive culture) or unknown reasons. The number of products collected and infused on average per month was 544, while the number of products that were not infused each month averaged 14. Figure 1 shows the number of products infused, pending and not infused each month. We hypothesized that as TCs and apheresis centers became more adept at cryopreservation and infusing cryopreserved products, fewer products not infused would decrease. To determine if there was a difference in the number of products that were not infused in the first half of the pandemic compared to the latter half of the pandemic, we compared the first 5 months (March-July 2020) to the last 5 months (March-July 2021) using the Kruskal-Wallis test to compare the two timeframes. As shown in Figure 2, a significant downward trend (p<0.04) was noted in non-infused products by domestic TCs (p<0.02), but not international TCs, most likely reflecting low volume from the international TCs. In the study cohort, we were also able to analyze the effect of COVID-19 on product infusion. Since March 2020, a total of 34 COVID-19 positive cases were noted with 33 being PCR positive and one being antibody positive. In the PCR positive cases, 16 had a donor that tested positive for COVID-19 post-donation: 12 products were infused and 4 were not infused based on the TC's preference. Thirteen (13) had a donor with COVID-19 concerns that caused the collection to be stopped and 4 were uncharacterized. In the patients that had products infused, there were no known infections of COVID-19 or deleterious effects on engraftment. Taken together this analysis demonstrates that despite cryopreservation, a surprisingly low number of products were not infused. Moreover, patients that received products from a COVID-19 positive donor did not become infected with COVID-19 nor suffered deleterious effects. This preliminary data may help inform donors to aid them in making choices about donation as well as guide TCs and donor centers in future crises or instances when a donor's allogeneic products need to be cryopreserved [Formula presented] Disclosures: Stefanski: Novartis: Honoraria. Devine: Magenta Therapeutics: Current Employment, Research Funding;Tmunity: Current Employment, Research Funding;S nofi: Consultancy, Research Funding;Johnsonand Johnson: Consultancy, Research Funding;Orca Bio: Consultancy, Research Funding;Be the Match: Current Employment;Vor Bio: Research Funding;Kiadis: Consultancy, Research Funding.